Mechanism of Toxic Cell Death

Question 1

What are the mechanisms of toxic cell death?

Answer 1

Impaired ATP synthesis; alteration of Ca gradients; other mechanisms–damage to cell membrane, cytoskeleton, or protein synthesis

Question 2

How can ATP synthesis be impaired?

Answer 2

interfering with delivery of electrons; delivery of oxygen; ETC function; ATP synthase inhibition; uncouplers

Question 3

what impairs delivery of electrons?

Answer 3

i. Fluoracetate–inhibits aconitase in the CAC
ii. Used as to kill rodents
Can’t deliver e-s to ETC–>no ATP production

Question 4

what impairs delivery of oxygen?

Answer 4

i. Carbon monoxide
ii. Outcompetes O2 for hemoglobin
iii. Blocks delivery of O2 to mitochondria for the ETC

Question 5

what impairs ETC function?

Answer 5

i. E.g. cyanide
1) Inhibits cytochrome oxidase
ii. E.g. rotenone–inhibits NADH coenzyme Q reducase

Question 6

what inihibts ATP synthase?

Answer 6

d. Chlordecone
i. Insectiside
Same class as DDT–can’t phos ADP to ATP

Question 7

what are the uncouplers?

Answer 7

i. Disrupt proton gradient
ii. E.g. pesticide called pentachlorophenol (PCPs)
iii. Fungicide
iv. Dinitrophenols

Question 8

what is pentachlorophenol?

Answer 8

???

Question 9

what are fungicides and how do they disturb cell membranes?

Answer 9

iii. Fungicide
1) Treating for lumber
2) Washes off into streams, kills fish
3) “ionophore”–makes membrane leaky to protons

Question 10

what are dinitrophenols?

Answer 10

1) Donate protons in inner mitochondrial space

Reduce the gradient

Question 11

alteration of Ca gradients

Answer 11

iv. 10 000x more ECF Ca than ICF Ca
1) When you open up the Ca “dam”, Ca floods in
v. Main mechanism: xenos alter plasma membrane permeability to Ca
1) Damage to membrane, to active transport that pumps Ca out
Major target: mitochondrial Ca (not SR Ca

Question 12

how do nonpolar solvents cause toxic cell death?

Answer 12

1) Lipid sol solvents
2) Alter the fluidity of membrane
a) E.g. like cholesterol

Question 13

how can the cytoskeleton be destroyed?

Answer 13

1) Scaffolding

2) Cholchecine–destroys spindle fibres (important in cell divison–inhibits mitosis)

Question 14

how can protein synthesis be interfered with?

Answer 14

1) Ethanol
a) This is why you don’t take tylenol with a hangover
b) If you have been binge drinking, protein synthesis has been shut down–>especially glutathione